Treatment of skin lesions and pruritus in prurigo nodularis patients

ABSTRACT

Disclosed herein are methods for selectively treating pruritus in a subject having chronic prurigo (CP), including prurigo nodularis (PN), pharmaceutical compositions for use in the treatment of pruritus in a subject having CP or PN, uses of nemolizumab or an equivalent thereof in the manufacture of a medicament for the treatment of pruritus in a subject having CP or PN.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/773,538 filed Jan. 27, 2020, which application claims priority under35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/797,803 filedJan. 28, 2019, and U.S. Provisional Application No. 62/809,404 filedFeb. 22, 2019, the entire contents of which are all incorporated hereinby reference.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been filedelectronically in ASCII format and is hereby incorporated by referencein its entirety. Said ASCII copy, created on Jan. 27, 2020, is named105153-3002_SEQ_LST.txt and is 30 kilobytes in size.

FIELD

Described herein are methods for treating skin lesions and pruritus of asubject having chronic prurigo (CP), including prurigo nodularis (PN),pharmaceutical compositions for use in the treatment of skin lesions andpruritus in a subject having CP, uses of nemolizumab or an equivalentthereof in the manufacture of a medicament for the treatment of skinlesions and pruritus in a subject having CP.

BACKGROUND

The following discussion is provided to aid the reader in understandingthe disclosure and is not admitted to describe or constitute prior artthereto.

Chronic prurigo (CP) is a skin disease due to neuronal sensitization toitch and development of an itch-scratch cycle. Prurigo nodularis (PN), asubtype of CP, and is a skin disease that causes hard, itchy lumps(nodules) to form on the skin. The itching (pruritus) can be intense,causing people to scratch themselves to the point of bleeding or pain.Scratching can cause more skin lesions to appear. The itching isworsened by heat, sweating, or irritation from clothing. In some cases,people with PN have a history of other diseases including eczema (atopicdermatitis), diabetes, lymphoma, HIV infection, severe anemia, or kidneydisease.

The exact cause of CP or PN is unknown. Although scratching is known tocause more nodules to appear, it is unclear what causes the itching todevelop in the first place. Diagnosis of the disease is based onobserving signs such as extremely itchy skin with the formation ofnodules. In some cases, a skin biopsy is used to confirm the diagnosis.Currently treatment may include corticosteroid creams, oral medications,cryotherapy, or photochemotherapy.

There remains a need to develop novel therapeutic regimes to treatpatients with PN, particularly those suffering from chronic pruritus.

SUMMARY

Provided herein are methods for treating skin lesions and pruritus in asubject having chronic prurigo (CP) including prurigo nodularis (PN),pharmaceutical compositions for use in the treatment of skin lesions andpruritus in a subject having CP including PN, uses of nemolizumab or anequivalent thereof in the manufacture of a medicament for the treatmentof skin lesions and pruritus in a subject having CP including PN.

In accordance with some embodiments, there are provided methods oftreating skin lesions and pruritus in a subject having CP, the methodcomprising, consisting of, or consisting essentially of administering aneffective amount of nemolizumab or an equivalent thereof to the subject.

In some embodiments of the methods, the subject has prurigo nodularis(PN). In some embodiments of the methods, the subject has been diagnosedof PN for at least about 6 months. In particular embodiments of themethods, the subject has at least about 20 nodules on his/her body witha bilateral distribution. In particular embodiments of the methods, thesubject has prurigo lesions on upper limbs, with or without lesions onthe trunk or lower limbs. In particular embodiments of the methods, thepruritus has been assigned a score of at least 4, while in someembodiments the pruritus has been assigned a score of at least 7 on theNumerical Rating Scale (NRS). In particular embodiments of the methods,the mean of the worst daily intensity of the NRS score is at least 7over the previous 3 days. In other particular embodiments of themethods, the mean of the worst daily intensity of the NRS score is atleast 7 over the previous week.

In some embodiments of the methods, the subject does not have atopicdermatitis. In some embodiments of the methods, the subject does nothave chronic pruritus resulting from a condition other than PN, such asscabies, insect bite, lichen simplex chronicus, psoriasis, acne,folliculitis, habitual picking, lymphomatoid papulosis, chronic actinicdermatitis, dermatitis herpetiformis, sporotrichosis, bullous disease.In some embodiments of the methods, the subject does not haveneuropathic or psychogenic pruritus, such as notalgia paresthetica,brachioradial pruritus, dilutional parasitosis, pathomimia.

In some embodiments of the methods, the effective amount of nemolizumabor the equivalent thereof ranges from about 0.01 mg/kg to about 0.1mg/kg, about 0.1 mg/kg to about 0.5 mg/kg, about 0.5 mg/kg to about 1.5mg/kg, about 1.5 mg/kg to about 2.5 mg/kg, or about 2.5 mg/kg to about10 mg/kg. In particular embodiments, the effective amount of nemolizumabor the equivalent thereof is about 0.1 mg/kg, about 0.5 mg/kg, about 1mg/kg, about 1.5 mg/kg, about 2 mg/kg, or about 2.5 mg/kg. In particularembodiments, the effective amount of nemolizumab or the equivalentthereof is a 40 mg flat dose. In other particular embodiments, theeffective amount of nemolizumab or equivalent thereof is 30 mg with a 60mg loading dose. In other particular embodiments, the effective amountof nemolizumab or the equivalent thereof is 6 60 mg flat dose,administered once every 4 weeks. In some embodiments of the methods, thenemolizumab or the equivalent thereof is administered by a topical orparenteral route. In some embodiments of the methods, the nemolizumab orthe equivalent thereof is administered subcutaneously. In someembodiments, the nemolizumab or the equivalent thereof is administeredonce per week, once every two weeks, once every three weeks, once everyfour weeks, once every five weeks, once every six weeks, once everyseven weeks, or once every eight weeks. In certain embodiments, thenumolizumab is administered over a period of at least 2 weeks, 3 weeks,1 month, 1.5 months, 2 months, 3 months, 4 months, 5 months, 6 months orlonger.

In accordance with some embodiments, there are provided pharmaceuticalcompositions for use in the treatment of skin lesion and pruritus in asubject having chronic prurigo (CP), the composition comprising,consisting of, or consisting essentially of nemolizumab or an equivalentthereof.

In some embodiments of the pharmaceutical compositions, the subject hasprurigo nodularis (PN). In some embodiments of the compositions, thesubject has been diagnosed of PN for at least about 6 months. Inparticular embodiments of the compositions, the subject has at leastabout 20 nodules on his/her body with a bilateral distribution. Inparticular embodiments of the compositions, the subject has prurigolesions on upper limbs, with or without lesions on the trunk or lowerlimbs. In particular embodiments of the compositions, the pruritus hasbeen assigned a score of at least 4, while in some embodiments thepruritus has been assigned a score of at least 7 on the Numerical RatingScale (NRS). In particular embodiments of the compositions, the mean ofthe worst daily intensity of the NRS score is at least 7 over theprevious 3 days. In other particular embodiments of the compositions,the mean of the worst daily intensity of the NRS score is at least 7over the previous week.

In some embodiments of the pharmaceutical compositions, the subject doesnot have atopic dermatitis. In some embodiments of the compositions, thesubject does not have chronic pruritus resulting from a condition otherthan PN, such as scabies, insect bite, lichen simplex chronicus,psoriasis, acne, folliculitis, habitual picking, lymphomatoid papulosis,chronic actinic dermatitis, dermatitis herpetiformis, sporotrichosis,bullous disease. In some embodiments of the compositions, the subjectdoes not have neuropathic or psychogenic pruritus, such as notalgiaparesthetica, brachioradial pruritus, dilutional parasitosis,pathomimia.

In some embodiments, the pharmaceutical composition further comprises acarrier. In some embodiments, the carrier is a pharmaceuticallyacceptable carrier.

In some embodiments of the pharmaceutical compositions, the nemolizumabor equivalent thereof is administered according to a flat dosingregimen, while in some embodiments the nemolizumab or equivalent thereofis administered according to a loading dose regimen, in which theloading dose may be higher than the subsequent serial doses (e.g., a 60mg loading dose followed by 30 mg serial doses).

In some embodiments of the pharmaceutical compositions, the nemolizumabor equivalent thereof is administered at a dose of about 0.01 mg/kg toabout 0.1 mg/kg, about 0.1 mg/kg to about 0.5 mg/kg, about 0.5 mg/kg toabout 1.5 mg/kg, about 1.5 mg/kg to about 2.5 mg/kg, or about 2.5 mg/kgto about 10 mg/kg. while in some embodiments, the nemolizumab orequivalent thereof is administered at a dose of about 10 mg, about 15mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg,about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg of nemolizumabor the equivalent thereof.

In accordance with some embodiments, there are provided uses ofnemolizumab or an equivalent thereof in the manufacture of a medicamentfor the treatment of pruritus in a subject having PN.

In some embodiments of the uses, the pruritus is moderate to severe. Insome embodiments of the uses, the subject has been diagnosed of PN forat least 6 months. In particular embodiments of the uses, the subjecthas at least 20 nodules on his/her body with a bilateral distribution.In particular embodiments of the uses, the subject has prurigo lesionson upper limbs, with or without lesions on the trunk or lower limbs. Inparticular embodiments of the uses, pruritus has been assigned a scoreof at least 4, while in some embodiments the pruritus has been assigneda score of at least 7 on the Numerical Rating Scale (NRS). In particularembodiments of the uses, the mean of the worst daily intensity of theNRS score is at least 7 over the previous 3 days. In other particularembodiments of the uses, the mean of the worst daily intensity of theNRS score is at least 7 over the previous week.

In some embodiments of the uses, the subject does not have atopicdermatitis. In some embodiments of the uses, the subject does not havechronic pruritus resulting from a condition other than PN, such asscabies, insect bite, lichen simplex chronicus, psoriasis, acne,folliculitis, habitual picking, lymphomatoid papulosis, chronic actinicdermatitis, dermatitis herpetiformis, sporotrichosis, bullous disease.In some embodiments of the uses, the subject does not have neuropathicor psychogenic pruritus, such as notalgia paresthetica, brachioradialpruritus, dilutional parasitosis, pathomimia.

In some embodiments of the uses, the nemolizumab or equivalent thereofis administered according to a flat dosing regimen, while in someembodiments the nemolizumab or equivalent thereof is administeredaccording to a loading dose regimen, in which the loading dose may behigher than the subsequent serial doses (e.g., a 60 mg loading dosefollowed by 30 mg serial doses).

In some embodiments of the uses, the nemolizumab or equivalent thereofis administered at a dose of about 0.01 mg/kg to about 0.1 mg/kg, about0.1 mg/kg to about 0.5 mg/kg, about 0.5 mg/kg to about 1.5 mg/kg, about1.5 mg/kg to about 2.5 mg/kg, or about 2.5 mg/kg to about 10 mg/kg.while in some embodiments, the nemolizumab or equivalent thereof isadministered at a dose of about 10 mg, about 15 mg, about 20 mg, about25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about80 mg, about 85 mg, about 90 mg of nemolizumab or the equivalentthereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 Overview of the clinical study of treating pruritus in patienthaving prurigo nodularis (PN) with nemolizumab. A multi-center (20 sitesin EU & US), randomized, double-blinded, placebo-controlled, parallelgroup study was conducted with approximately 70 randomized patients in 2arms (35 per arm) were conducted, and stratified on background of atopy.Enrolled patients received nemolizumab or placebo at a dose of 0.5 mg/kgevery 4 weeks from baseline to Week 8.

FIG. 2 illustrates percentage change from baseline in weekly averagepeak pruritus numerical rating score (NRS) at Week 4.

FIG. 3 illustrates percentage change from baseline in weekly averagepeak pruritus NRS over 18 weeks.

FIG. 4 illustrates absolute change from baseline in weekly average peakpruritus NRS over 18 weeks.

FIG. 5 illustrates absolute change from baseline in weekly average peakpruritus NRS over 18 weeks in patients with no atopy.

FIG. 6 illustrates absolute change from baseline in weekly average peakpruritus NRS over 18 weeks in patients with atopy.

FIG. 7 illustrates proportion of subjects achieving Investigators'Global Assessment (IGA) success (0/1). Investigators' Global Assessment(IGA) scores range from 0 (clear) to 4 (severe disease) and arepresented as a percentage of patients in the indicated population.

FIG. 8 illustrates IGA distribution in patients over 18 weeks treatment.

FIG. 9 illustrates percentage change in verbal rating scale (VRS) over18 week treatment. The verbal rating scale (VRS) is a monodimensionalscale that allows patients to describe their itch intensity by means ofgradually rising adjectives.

FIG. 10 illustrates dermatology life quality index (DLQI) Responders(≥4) at Week 4 and Week 12. Dermatology Life Quality Index (DLQI) scoresrange from 0 to 30, with higher scores indicating a lower quality oflife.

FIG. 11 illustrates change from baseline in DLQI at Week 4 and Week 12.

FIGS. 12A-12D compares full body image of patients before nemolizumabtreatment (A and C) and after treatment for 16 weeks (B and D).

FIGS. 13A-13D compares full body image of patients before nemolizumabtreatment (A and C) and after treatment for 16 weeks (B and D).

FIGS. 14A-14D compares full body image of patients before nemolizumabtreatment (A and C) and after treatment for 16 weeks (B and D).

FIG. 15 illustrates percentage change in average pruritus NumericalRating Scale (NRS) over 18 week treatment.

FIG. 16 illustrates proportion of subjects with Prurigo Activity Score(PAS) 75% healed over 18 week treatment.

FIG. 17 illustrates proportion of subjects with Prurigo Activity Score(PAS) 50% healed over 18 week treatment.

FIG. 18 illustrates proportion of subjects with Prurigo Activity Score(PAS) 0-24% healed over 18 week treatment.

FIG. 19 illustrates percentage change from baseline in sleep disturbanceNRS at week 4.

FIG. 20 illustrates percentage change in sleep disturbance NRS at week4.

DETAILED DESCRIPTION

Embodiments according to the present disclosure will be described morefully hereinafter. Aspects of the disclosure may, however, be embodiedin different forms and should not be construed as limited to theembodiments set forth herein. Rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art. Theterminology used in the description herein is for the purpose ofdescribing particular embodiments only and is not intended to belimiting.

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the present applicationand relevant art and should not be interpreted in an idealized or overlyformal sense unless expressly so defined herein. While not explicitlydefined below, such terms should be interpreted according to theircommon meaning.

The terminology used in the description herein is for the purpose ofdescribing particular embodiments only and is not intended to belimiting of the invention. All publications, patent applications,patents and other references mentioned herein are incorporated byreference in their entirety.

Unless the context indicates otherwise, it is specifically intended thatthe various features of the invention described herein can be used inany combination. Moreover, the disclosure also contemplates that in someembodiments, any feature or combination of features set forth herein canbe excluded or omitted. To illustrate, if the specification states thata complex comprises components A, B and C, it is specifically intendedthat any of A, B or C, or a combination thereof, can be omitted anddisclaimed singularly or in any combination.

Unless explicitly indicated otherwise, all specified embodiments,features, and terms intend to include both the recited embodiment,feature, or term and biological equivalents thereof.

Definitions

As used herein, the singular forms “a,” “an,” and “the” designate boththe singular and the plural, unless expressly stated to designate thesingular only.

It is to be understood, although not always explicitly stated, that allnumerical designations are preceded by the term “about.” The term“about” means that the number comprehended is not limited to the exactnumber set forth herein, and is intended to refer to numberssubstantially around the recited number while not departing from thescope of the invention. As used herein, “about” will be understood bypersons of ordinary skill in the art and will vary to some extent on thecontext in which it is used. If there are uses of the term which are notclear to persons of ordinary skill in the art given the context in whichit is used, “about” will mean up to plus or minus 15%, 10%, 5%, 1%, or0.1% of the particular term.

Also as used herein, “and/or” refers to and encompasses any and allpossible combinations of one or more of the associated listed items, aswell as the lack of combinations when interpreted in the alternative(“or”).

The terms “administer,” “administration,” or “administering” as usedherein refer to (1) providing, giving, dosing and/or prescribing, suchas by either a health professional or his or her authorized agent orunder his direction, and (2) putting into, taking or consuming, such asby a health professional or the subject. Administration shall includewithout limitation, administration by oral, parenteral (e.g.,intramuscular, intraperitoneal, intravenous, ICV, intracisternalinjection or infusion, subcutaneous injection, or implant), byinhalation spray nasal, vaginal, rectal, sublingual, urethral (e.g.,urethral suppository) or topical routes of administration (e.g., gel,ointment, cream, aerosol, etc.) and can be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants, excipients,and vehicles appropriate for each route of administration. The inventionis not limited by the route of administration, the formulation or dosingschedule.

The terms “treat”, “treating” or “treatment”, as used herein, includealleviating, abating or ameliorating PN, pruritus, or one or moresymptoms thereof, whether or not PN and/or pruritus is considered to be“cured” or “healed” and whether or not all symptoms are resolved. Theterms also include reducing or preventing progression of PN and/orpruritus or one or more symptoms thereof, impeding or preventing anunderlying mechanism of PN and/or pruritus or one or more symptomsthereof, and achieving any therapeutic and/or prophylactic benefit.

Interleukin 31 receptor subunit alpha (“IL-31RA,” also known as NR10,glm-r, and GPL) is a protein that forms a heterodimer with oncostatin Mreceptor (OSMR) and functions as an IL-31 receptor. There are multipleknown splicing variants of human-derived IL-31RA (WO 00/075314): NR10.1consists of 662 amino acids and contains a transmembrane domain. NR10.2is a soluble receptor-like protein consisting of 252 amino acids withoutthe transmembrane domain. Meanwhile, known IL-31RA splicing variantsthat function as transmembrane receptor proteins include NR10.3 andIL-31RAv3. Preferred IL-31RA variants include NR10.3 (also referred toas ILRAv4 (Nat Immunol 5, 752-60, 2004) and IL-31RAv3. NR 10.3(IL31RAv4) consists of 662 amino acids (WO 00/075314; Nat Immunol 5,752-60, 2004) and IL31RAv3 consists of 732 amino acids (GenBankAccession No: NM-139017).

(SEQ ID NO: 1) MKLSPQPSCVNLGMMWTWALWMLPSLCKFSLAALPAKPENISCVYYYRKNLTCTWSPGKETSYTQYTVKRTYAFGEKHDNCTTNSSTSENRASCSFFLPRITIPDNYTIEVEAENGDGVIKSHMTYWRLENIAKTEPPKIFRVKPVLGIKRMIQIEWIKPELAPVSSDLKYTLRFRTVNSTSWMEVNFAKNRKDKNQTYNLTGLQPFTEYVIALRCAVKESKFWSDWSQEKMGMTEEEAPCGLELWRVLKPAEADGRRPVRLLWKKARGAPVLEKTLGYNIWYYPESNTNLTETMNTTNQQLELHLGGESFWVSMISYNSLGKSPVATLRIPAIQEKSFQCIEVMQACVAEDQLVVKWQSSALDVNTWMIEWFPDVDSEPTTLSWESVSQATNWTIQQDKLKPFWCYNISVYPMLHDKVGEPYSIQAYAKEGVPSEGPETKVENIGVKTVTITWKEIPKSERKGIICNYTIFYQAEGGKGFSKTVNSSILQYGLESLKRKTSYIVQVMASTSAGGTNGTSINFKTLSFSVFEIILITSLIGGGLLILIILTVAYGLKKPNKLTHLCWPTVPNPAESSIATWHGDDFKDKLNLKESDDSVNTEDRILKPCSTPSDKLVIDKLVVNFGNVLQEIFTDEARTGQENNLGGEKNGTRILSSCPTSI

The amino acid sequence of IL31RAv4 is:

(SEQ ID NO: 2) MMWTWALWMLPSLCKFSLAALPAKPENISCVYYYRKNLTCTWSPGKETSYTQYTVKRTYAFGEKHDNCTTNSSTSENRASCSFFLPRITIPDNYTIEVEAENGDGVIKSHMTYWRLENIAKTEPPKIFRVKPVLGIKRMIQIEWIKPELAPVSSDLKYTLRFRTVNSTSWMEVNFAKNRKDKNQTYNLTGLQPFTEYVIALRCAVKESKFWSDWSQEKMGMTEEEAPCGLELWRVLKPAEADGRRPVRLLWKKARGAPVLEKTLGYNIWYYPESNTNLTETMNTTNQQLELHLGGESFWVSMISYNSLGKSPVATLRIPAIQEKSFQCIEVMQACVAEDQLVVKWQSSALDVNTWMIEWFPDVDSEPTTLSWESVSQATNWTIQQDKLKPFWCYNISVYPMLHDKVGEPYSIQAYAKEGVPSEGPETKVENIGVKTVTITWKEIPKSERKGIICNYTIFYQAEGGKGFSKTVNSSILQYGLESLKRKTSYIVQVMASTSAGGTNGTSINFKTLSFSVFEIILITSLIGGGLLILIILTVAYGLKKPNKLTHLCWPTVPNPAESSIATWHGDDFKDKLNLKESDDSVNTEDRILKPCSTPSDKLVIDKLVVNFGNVLQEIFTDEARTGQENNLGGEKNGYVTCPFRPDCPLGKSFEELPVSPEIPPRKSQYLRSRMPEGTRPEAKEQLLFSGQSLVPDHLCEEGAPNPYLKNSVTAREFLVSEKLPEHTKGEV

Mouse-derived IL-31RA includes proteins comprising the amino acidsequence:

(SEQ ID NO: 3) MWTLALWAFSFLCKFSLAVLPTKPENISCVEYFDRNLTCTWRPEKETNDTSYIVTLTYSYGKSNYSDNATEASYSFPRSCAMPPDICSVEVQAQNGDGKVKSDITYWHLISIAKTEPPIILSVNPICNRMFQIQWKPREKTRGFPLVCMLRERTVNSSRWTEVNFENCKQVCNLTGLQAFTEYVLALRFRFNDSRYWSKWSKEETRVTMEEVPHVLDLWRILEPADMNGDRKVRLLWKKARGAPVLEKTEGYHIQYFAENSTNLTEINNITTQQYELLLMSQAHSVSVTSENSLGKSQEAILRIPDVHEKTFQYIKSMKAYIAEPLLVVNWQSSIPAVDTWIVEWLPEAAMSKFPALSWESVSQVTNWTIEQDKLKPFTCYNISVYPVLGHRVGEPYSIQAYAKEGTPLKGPETRVENIGLRTATITWKEIPKSARNGFINNYTVEYQAEGGKELSKTVNSHALQCDLESLTRRTSYTVWVMASTRAGGTNGVRINFKTLSISVFEIVLLTSLVGGGLLLLSIKTVTFGLRKPNRLTPLCCPDVPNPAESSLATWLGDGEKKSNMKETGNSGDTEDVVLKPCPVPADLIDKLVVNFENFLEVVLTEEAGKGQASILGGEANEYVTSPSRPDGPPGKSEKEPSVLTEVASEDSHSTCSRMADEAYSELARQPSSSCQSPGLSPPREDQAQNPYLKNSVTTREFLVHENIPEHSKGEV

Cynomolgus monkey-derived IL-31RA includes proteins comprising the aminoacid sequence:

(SEQ ID NO: 4) MMWTWALWMFPLLCKFGLAALPAKPENISCVYYYRKNLTCTWSPGKETSYTQYTAKRTYAFGKKHDNCTTSSSTSENRASCSFFLPRITIPDNYTIEVEAENGDGVIKSDMTCWRLEDIAKTEPPEIFSVKPVLGIKRMIRIEWIKPELAPVSSDLKYALRFRTVNSTSWMEVNFAKNRKDTNQTYNLMGLQAFTEYVVALRCAVKESKFWSDWSQEKMGMTEEEAPCGLELWRVLKPTEVDGRRPVRLLWKKARGAPVLEKTLGYNIWYFPENNTNLTETVNTTNQQLELHLGGESYWVSMISYNSLGKSPVTTLRIPAIQEKSFRCIEVMQACLAEDQLVVKWQSSALDVNTWMIEWFPDMDSEHPTLSWESVSQATNWTIQQDKLKPFWCYNTSVYPMLHDKVGEPYSIQAYAKEGIPSKGPETKVENTGVKTVTITWKETPKSERKGIICNYTIFYQAEGGKGFSKTVNSSILQYGLESLKRKTSYTVRVMASTSAGGINGTSINFKTLSFSVFETTLITSLIGGGLLILTILTVAYGLKKPNKLTHLCWPSVPNPAESSIATWRGDDFKDKLNLKESDDSVNTEDRILKPCSTPSDKLVIDKSVVNFGNVLQEMFTDEARTGQENNLGGEKNEYVTHPFRADCPLGKSFEELPVSPEIPPRKSQYLRSRMPEGTCLEAEEQLLVSGQSLESLAPDHVREAAAPNPYLKNSVTTREFLVSQKLPEHTKGEV

As used herein, the term “subject” is used interchangeably with“patient,” and indicates a mammal, in particular a human, equine,bovine, porcine, feline, canine, murine, rat, or non-human primate. Inpreferred embodiments, the subject is a human. In some embodiments, thesubject has been diagnosed of PN for at least 6 months. In particularembodiments, the subject has at least 20 nodules on his/her body with abilateral distribution. In particular embodiments, the subject hasprurigo lesions on upper limbs, with or without lesions on the trunk orlower limbs. In particular embodiments, the subject has pruritus thathas been assigned a score of at least 7 on the Numerical Rating Scale(NRS). In particular embodiments, the mean of the worst daily intensityof the NRS score is at least 7 over the previous 3 days. In otherparticular embodiments, the mean of the worst daily intensity of the NRSscore is at least 7 over the previous week.

In some embodiments, the subject does not have atopic dermatitis. Insome embodiments, the subject does not have chronic pruritus resultingfrom a condition other than PN, such as scabies, insect bite, lichensimplex chronicus, psoriasis, acne, folliculitis, habitual picking,lymphomatoid papulosis, chronic actinic dermatitis, dermatitisherpetiformis, sporotrichosis, bullous disease. In some embodiments, thesubject does not have neuropathic or psychogenic pruritus, such asnotalgia paresthetica, brachioradial pruritus, dilutional parasitosis,pathomimia.

The term “chronic prurigo” or (“CP”) is used herein as it is in the artand means a distinct disease defined by the presence of chronic pruritusand multiple localized or generalized pruriginous lesions. Chronicpruritic condition is characterized by excoriated, scaled or crustedplaques and/or papules and/or nodules, often with a whitish or pinkcenter and hyperpigmented border and scars. There are four subtypes ofchronic pruritus: nodular type (prurigo nodularits or PN), popular type(papular prurigo), plaque type, and umbilicated type (Kyrle type). CPoccurs due to a neuronal sensitization to itch and the development of anitch-scratch cycle. CP can be of dermatological, systemic, neurologic,psychiatric/psychosomatic, multifactorial or undetermined origin. Theterm CP includes all stages and manefestations of chronic prurigo. Thebest known subtype of CP is prurigo nodularis (PN). See Pereira et al.,Journal of European Academy of Dermatology and Venereology (2018)32:1059-1065.

The term “prurigo nodularis” (or “PN”) is used herein as it is in theart and means a skin disease that causes hard, itchy lumps (nodules) toform on the skin. The itching (pruritus) can be intense, causing peopleto scratch themselves to the point of bleeding or pain. Scratching cancause more skin lesions to appear. The itching is worsened by heat,sweating, or irritation from clothing. In some cases, people with PNhave a history of other diseases including eczema (atopic dermatitis),diabetes, lymphoma, HIV infection, severe anemia, or kidney disease. Theexact cause of PN is not well-understood. It is thought that nodules aremore likely to form when skin has been scratched or irritated in someway. Therefore, the act of a person scratching skin can cause thenodules to form. However, the cause of the skin to originally becomeintensely itchy is unclear. Many people with PN have a history of eczema(atopic dermatitis), other skin conditions, or allergies. The mainsymptom of prurigo nodularis (PN) is the formation of hard, very itchylumps (nodules) on the skin. The nodules can range in size from verysmall to about half an inch in diameter. The nodules often have a rough,dry top and can range in number from a few to hundreds. Nodules mostcommonly form on the outer arms, shoulders, and legs. Nodules can alsoform on the neck and trunk, and they rarely form on the face and palms.They may be lighter or darker in color than the surrounding skin.Scarring may occur after nodules begin to heal. The symptoms of PN canbegin at any age but are most common in adults between 20-60 years.People who have PN may become very concerned about the appearance of thenodules, and the intensely itchy skin may interfere with sleep or witheveryday activities. This can cause people with PN to develop stress anddepression.

The term “pruritus” is used herein as it is in the art and refers toitchy skin and/or an itch sensation. Pruritus may be caused by PN orother diseases or conditions such as dry skin. In some cases, pruritusinvolves generalized itchy skin over the whole body. In some cases,pruritus is localized to specific regions of the body such as on an armor leg. Pruritus can be chronic or acute. Symptoms of pruritus includebut are not limited to skin excoriations, redness, bumps, spots,blisters, dry skin, cracked skin, and leathery or scaly texture to theskin. In some cases, pruritus does not result in detectable changes tothe skin. Behavioral responses to pruritus include but are not limitedto skin scratching and/or skin massage. In some cases, skin scratchingcan result in excoriations that range from mild to severe. In somecases, patients with pruritus abstain from scratching and/or massagingthe skin. Traditional treatments for pruritus include but are notlimited to skin moisturizers, topical emollients, antihistamines such asdiphenhydramine, corticosteroids such as hydrocortisone topical cream,counterirritants such as mint oil, menthol, or camphor, crotamiton, anantipruritic agent often used to treat scabies, local anesthetics suchas benzocaine topical cream, and phototherapy. The common type of lightused for phototherapy is UVB.

As used herein, the term “antibody” collectively refers toimmunoglobulins or immunoglobulin-like molecules including by way ofexample and without limitation, IgA, IgD, IgE, IgG and IgM, combinationsthereof or fragments thereof. Fragments of antibodies including, by wayof example and without limitation, Fab fragments and single chainvariable fragments (scFv), and similar molecules produced during animmune response in any vertebrate, for example, in mammals such ashumans, goats, rabbits and mice, as well as non-mammalian species, suchas shark immunoglobulins.

In terms of antibody structure, an immunoglobulin generally has heavy(H) chains and light (L) chains interconnected by disulfide bonds. Thereare two types of light chain, lambda (λ) and kappa (κ). There are fivemain heavy chain classes (or isotypes) which determine the functionalactivity of an antibody molecule: IgM, IgD, IgG, IgA and IgE. Each heavyand light chain contains a constant region and a variable region, (theregions are also known as “domains”). In combination, the heavy and thelight chain variable regions, also called the “Fab region,” specificallybind the antigen. Light and heavy chain variable regions contain a“framework” region interrupted by three hypervariable regions, alsocalled “complementarity-determining regions” or “CDRs”. The extent ofthe framework region and CDRs has been defined (see, Kabat et al.,Sequences of Proteins of Immunological Interest, U.S. Department ofHealth and Human Services, 1991, which is hereby incorporated byreference). The Kabat database is now maintained online. The sequencesof the framework regions of different light or heavy chains arerelatively conserved within a species. The framework region of anantibody, that is the combined framework regions of the constituentlight and heavy chains, largely adopts a 3-sheet conformation and theCDRs form loops which connect, and in some cases form part of, the3-sheet structure. Thus, framework regions act to form a scaffold thatprovides for positioning the CDRs in correct orientation by inter-chain,non-covalent interactions.

The CDRs are primarily responsible for binding to an epitope of anantigen. The CDRs of each chain are typically referred to as CDR1, CDR2,and CDR3, numbered sequentially starting from the N-terminus, and arealso typically identified by the chain in which the particular CDR islocated. Thus, a V_(H) CDR3 is located in the variable domain of theheavy chain of the antibody in which it is found, whereas a V_(L) CDR1is the CDR1 from the variable domain of the light chain of the antibodyin which it is found. An antibody that binds IL-31RA will have aspecific V_(H) region and the V_(L) region sequence, and thus specificCDR sequences. Antibodies with different specificities (i.e. differentcombining sites for different antigens) have different CDRs. Although itis the CDRs that vary from antibody to antibody, only a limited numberof amino acid positions within the CDRs are directly involved in antigenbinding. These positions within the CDRs are called specificitydetermining residues (SDRs). The base of the antibody plays a role inmodulating immune cell activity. This region is called the Fc fragmentregion (Fc) and is composed of two heavy chains that contribute two orthree constant domains depending on the class of the antibody. The Fcregion functions to guarantee that each antibody generates anappropriate immune response for a given antigen, by binding to aspecific class of proteins found on certain cells, such as Blymphocytes, follicular dendritic cells, natural killer cells,macrophages, neutrophils, etc. and are call “Fc receptors.” Because theconstant domains of the heavy chains make up the Fc region of anantibody, the classes of heavy chain in antibodies determine their classeffects. The heavy chains in antibodies include alpha, gamma, delta,epsilon, and mu, and correlate to the antibody's isotypes IgA, G, D, E,and M, respectively. This infers different isotypes of antibodies havedifferent class effects due to their different Fc regions binding andactivating different types of receptors.

There are four subclasses of IgG, which is the most abundant antibodyisotype found in human serum. The four subclasses, IgG1, IgG2, IgG3, andIgG4, which are highly conserved. See generally, world wide web:ncbi.nlm.nih.gov/pmc/articles/PMC4202688/. The amino acid sequence ofthe constant regions of these peptides are known in the art, e.g., seeRutishauser, U. et al. (1968) “Amino acid sequence of the Fc region of ahuman gamma G-immunoglobulin” PNAS 61(4):1414-1421; Shinoda et al.(1981) “Complete amino acid sequence of the Fc region of a human deltachain” PNAS 78(2):785-789; and Robinson et al. (1980) “Complete aminoacid sequence of a mouse immunoglobulin alpha chain (MOPC 511)” PNAS77(8):4909-4913.

Therapeutic Antibodies

“Nemolizumab” is a humanized monoclonal antibody that binds to IL-31RA.Nemolizumab is annotated as follows: immunoglobulin G2-kappa, anti-[Homosapiens IL31RA (interleukin 31 receptor subunit alpha)], humanizedmonoclonal antibody; gamma2 heavy chain (1-445) [humanized VH (Homosapiens IGHV1-2*02 (83.70%)-(IGHD)-IGHJ5*01) [8.8.14] (1-121)-Homosapiens IGHG2*01 (CH1 C10>S (135), R12>K (137), E16>G (141), S17>G (142)(122-219), hinge C4>S (223) (220-231), CH2 H30>Q (268) (232-340), CH3R11>Q (355), Q98>E (419) (341-445)) (122-445)], (224-214′)-disulfidewith kappa light chain (1′-214′) [humanized V-KAPPA (Homo sapiensIGKV1-39*01 (82.10%)-IGKJ4*01) [6.3.9] (1′-107′)-Homo sapiens IGKC*01(108′-214′)]; dimer (227-227″:230-230″)-bisdisulfide. Nemolizumab hasdisulfide bridges at the following locations: Intra-H (C23-C104) 22-96148-204 261-321 367-425 22″-96″ 148″-204″ 261″-321″ 367″-425″; Intra-L(C23-C104) 23′-88′ 134′-194′ 23′″-88′″ 134′″-194″; Inter-H-L (h 5-CL126) 224-214′ 224″-214′″; Inter-H-H (h 8, h 11) 227-227″ 230-230″.Nemolizumab has N-glycosylation sites at the following locations: H CH2N84.4: 297, 297″. Nemolizumab lacks H chain C-terminal glycine andlysine (CHS G1>del, K2>del).

Nemolizumab heavy chain amino acid sequence:

(SEQ ID NO: 5) QVQLVQSGAEVKKPGASVKVSCKASGYTFT

WVRQAPGQGLEWMG

RVTITADKSTSTAYMELSSLRSEDTAVYYCAR

WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKSCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSL SLSP

Nemolizumab light chain amino acid sequence:

(SEQ ID NO: 6) DIQMTQSPSSLSASVGDRVTITC

WYQQKPGKAPKWY

GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC

FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

The variable domains of the heavy and light chain sequences are shown inbold above, and the CDR sequences are underlined/italicized.

Equivalent antibodies to nemolizumab include but are not limited to: (i)antibodies with heavy chains comprising at least 55%, at least 65%, atleast 70%, at least 75%, at least 80%, at least 85%, at least 90%, atleast 95%, at least 97%, at least 98%, at least 99%, or 100% amino acidsequence identity to nemolizumab's heavy chain sequence, (ii) antibodieswith light chains comprising at least 55%, at least 65%, at least 70%,at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, atleast 97%, at least 98%, at least 99%, or 100% amino acid sequenceidentity to nemolizumab's light chain sequence, (iii) antibodies withvariable regions comprising at least 55%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95%, atleast 97%, at least 98%, at least 99%, or 100% amino acid sequenceidentity to nemolizumab's variable region sequences, (iv) antibodieswith CDRs comprising at least 55%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, at least 90%, at least 95%, at least97%, at least 98%, at least 99%, or 100% amino acid sequence identity tonemolizumab's CDR sequences, (v) antibodies that bind to the sameisoform of IL-31RA as nemolizumab (e.g., IL31-RAv3), optionally the sameepitope of IL-31RA, (vi) antibodies that block or neutralize IL-31RA,(vii) antibodies that bind to oncostatin M receptor (OSMR), and (viiii)combinations thereof. For example, suitable equivalents includeimmunoglobulins or immunoglobulin-like molecules with the same orsubstantially similar heavy and light chain amino acid sequences asnemolizumab. Additional exemplary nemolizumab equivalents are described,for example, in WO 2010/064697.

Equivalents of nemolizumab may be monoclonal or polyclonal antibodies.Such monoclonal antibodies having IL31-RA-binding and/or neutralizingactivity can be obtained, for example, by the following procedure:anti-IL31-RA monoclonal antibodies are prepared by using as an antigenIL31-RA or a fragment thereof that is derived from a mammal such ashuman or mouse by known methods, and then antibodies havingIL31-RA-binding and/or neutralizing activity are selected from the thusobtained anti-IL31-RA monoclonal antibodies. Specifically, a desiredantigen or cells expressing the desired antigen are used as asensitizing antigen for immunization according to conventionalimmunization methods. Anti-IL31-RA monoclonal antibodies can be preparedby fusing the obtained immune cells with known parental cells usingconventional cell fusion methods, and screening them for monoclonalantibody-producing cells (hybridomas) by conventional screening methods.Animals to be immunized include, for example, mammals such as mice,rats, rabbits, sheep, monkeys, goats, donkeys, cows, horses, and pigs.The antigen can be prepared using the known IL31-RA gene sequenceaccording to known methods, for example, by methods using baculovirus(for example, WO 98/46777).

Hybridomas can be prepared, for example, according to the method ofMilstein et al. (Kohler, G. and Milstein, C., Methods Enzymol. (1981)73: 3-46). When the immunogenicity of an antigen is low, immunizationmay be performed after linking the antigen with a macromolecule havingimmunogenicity, such as albumin. Antigens used to prepare monoclonalantibodies that have a binding and/or neutralizing activity againsthuman IL31-RA are not particularly limited, as long as they enablepreparation of antibodies that have a binding and/or neutralizingactivity against human IL31-RA. For example, it is known that there area number of variants of human IL31-RA, and any variant may be used as animmunogen as long as it enables preparation of antibodies that have abinding and/or neutralizing activity against human IL31-RA.Alternatively, under the same condition, a peptide fragment of IL31-RAor a protein in which artificial mutations have been introduced into thenatural IL31-RA sequence may be used as an immunogen. Human IL31-RA.3 isone of preferred immunogens in preparing antibodies that have anactivity of binding and/or neutralizing IL31-RA in the presentdisclosure.

The IL31-RA-binding activity of the equivalent antibodies can bedetermined by methods known to those skilled in the art. Methods fordetermining the antigen-binding activity of an antibody include, forexample, ELISA (enzyme-linked immunosorbent assay), EIA (enzymeimmunoassay), RIA (radioimmunoassay), and fluorescent antibody method.For example, when enzyme immunoassay is used, antibody-containingsamples, such as purified antibodies and culture supernatants ofantibody-producing cells, are added to antigen-coated plates. Asecondary antibody labeled with an enzyme, such as alkaline phosphatase,is added and the plates are incubated. After washing, an enzymesubstrate, such as p-nitrophenyl phosphate, is added, and the absorbanceis measured to evaluate the antigen-binding activity. The binding and/orneutralizing activity of an equivalent antibody against IL31-RA can bemeasured, for example, by observing the effect of suppressing the growthof the IL-31-dependent cell line. For example, the activity of apurified mouse IL-31 antibody can be assayed by assessing theIL-31-dependent growth of Ba/F3 cells transfected with mouse IL-31receptor a and mouse OSMR genes.

The inventors have hypothesized that an anti-pruritic drug could have agreater impact on PN in patients that suffer from moderate to severepruritus.

In some embodiments, pruritus are scored as none, mild, moderate, orsevere. “None,” “mild,” “moderate,” and “severe” are terms of art indescribing the presence, extent, and/or intensity of excoriations. Thoseof skill in the art know the metes and bounds of these terms.

In some embodiments, pruritus is characterized according to one or moreof the following methods known by those skilled in the art. For example,the intensity can be quickly measured with monodimensional scales thatare routinely used in clinical care. See Pereira et al., AllergologyInternational (2017) 66:3-78, incorporated herein by reference. Forexample, patients can be asked to rate their itch intensity from 0 (“noitch”) to 10 (“worst imaginable itch”) with the numerical rating scale(NRS). Another monodimensional scale, the visual analogue scale (VAS),provides patients with the opportunity to indicate the intensity oftheir itch by marking on a 10 cm long, ruler-shaped scale. Bothendpoints are marked with a number corresponding to the intensity, with0 representing “no itch” and 10 the “worst imaginable itch.” Scoresbelow 3.0 VAS/NRS points are generally associated with mild itch,whereas scores higher than 6.9 illustrate severe itch. Scores above 9.0represent a very severe itch. The verbal rating scale (VRS) is a furthermonodimensional scale that allows patients to describe their itchintensity by means of gradually rising adjectives (0—no itch, 4—worstimaginable itch). The NRS, VAS and VRS have been validated inlarge-scale studies consisting of chronic pruritus patients withpruritic dermatoses or pruritus of various origins. These instrumentshave high reproducibility and there was a high correlation betweenscales 6, 7, 8. Chronic pruritus can greatly reduce patient quality oflife. For this reason, Dermatology Life Quality Index (DLQI) is widelyused and has been validated. DLQI scores range from 0 to 30, with higherscores indicating a lower quality of life. Investigators' GlobalAssessment (IGA) scores range from 0 (clear) to 5 (very severe disease)and are presented as a percentage of patients in the indicatedpopulation. In the present study, IGA scores range from 0 to 4.

Pharmaceutical Compositions

Provided herein are pharmaceutical compositions for use in the treatmentof skin lesions and pruritus in in a subject having chronic prurigo(CP), the composition comprising, consisting of, or consistingessentially of nemolizumab or an equivalent thereof. Moreover, thepresent disclosure provides therapeutic agents for CP which comprisenemolizumab or an equivalent thereof as an active ingredient.

In some embodiments, the subject has prurigo nodularis (PN). In someembodiments, the subject has been diagnosed of PN for at least about 6months. In particular embodiments, the subject has at least about 20nodules on his/her body with a bilateral distribution. In particularembodiments, the subject has prurigo lesions on upper limbs, with orwithout lesions on the trunk or lower limbs. In particular embodiments,the pruritus has been assigned a score of at least 7 on the NumericalRating Scale (NRS). In particular embodiments, the mean of the worstdaily intensity of the NRS score is at least 7 over the previous 3 days.In other particular embodiments, the mean of the worst daily intensityof the NRS score is at least 7 over the previous week.

In some embodiments, the subject does not have atopic dermatitis. Insome embodiments, the subject does not have chronic pruritus resultingfrom a condition other than PN, such as scabies, insect bite, lichensimplex chronicus, psoriasis, acne, folliculitis, habitual picking,lymphomatoid papulosis, chronic actinic dermatitis, dermatitisherpetiformis, sporotrichosis, bullous disease. In some embodiments, thesubject does not have neuropathic or psychogenic pruritus, such asnotalgia paresthetica, brachioradial pruritus, dilutional parasitosis,pathomimia.

The phrase “comprise(s) nemolizumab or an equivalent thereof as anactive ingredient” means comprising nemolizumab or an equivalent thereofas at least one of the active ingredients, and does not limit theproportion of the antibody. In addition, the therapeutic agents for PNin the present disclosure may also comprise, in combination withnemolizumab or an equivalent thereof, other ingredients that enhance thetreatment of PN. For example, the composition may comprise one or moretopical corticosteroid creams or injections, ointments with menthol orphenol to cool and soothe itchy skin, capsaicin cream, oralcorticosteroids, selective serotonin reuptake inhibitors (SSRIs), andoral antihistamines.

Pharmaceutical compositions of nemolizumab or an equivalent thereof ofthe present disclosure can be prepared as formulations according tostandard methods (see, for example, Remington's Pharmaceutical Science,Mark Publishing Company, Easton, USA). In some embodiments, thepharmaceutical compositions comprise a carrier and/or additive. In someembodiments, the carrier is a pharmaceutically acceptable carrier. Forexample, in some embodiments, the pharmaceutical composition comprisesone or more surfactants (for example, PEG and Tween), excipients,antioxidants (for example, ascorbic acid), coloring agents, flavoringagents, preservatives, stabilizers, buffering agents (for example,phosphoric acid, citric acid, and other organic acids), chelating agents(for example, EDTA), suspending agents, isotonizing agents, binders,disintegrators, lubricants, fluidity promoters, corrigents, lightanhydrous silicic acid, lactose, crystalline cellulose, mannitol,starch, carmellose calcium, carmellose sodium, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylacetal diethylaminoacetate,polyvinylpyrrolidone, gelatin, medium chain fatty acid triglyceride,polyoxyethylene hydrogenated castor oil 60, sucrose,carboxymethylcellulose, corn starch, and inorganic salt. In someembodiments, the pharmaceutical composition comprises one or more otherlow-molecular-weight polypeptides, proteins such as serum albumin,gelatin, and immunoglobulin, and amino acids such as glycine, glutamine,asparagine, arginine, and lysine.

When nemolizumab or an equivalent thereof is prepared as an aqueoussolution for injection, nemolizumab or an equivalent thereof may bedissolved in an isotonic solution containing, for example, physiologicalsaline, dextrose, or other adjuvants. The adjuvants may include, forexample, D-sorbitol, D-mannose, D-mannitol, and sodium chloride. Inaddition, appropriate solubilizing agents, for example, alcohols (forexample, ethanol), polyalcohols (for example, propylene glycols andPEGs), and non-ionic detergents (polysorbate 80 and HCO-50) may be usedconcomitantly.

If necessary, nemolizumab or an equivalent thereof may be encapsulatedin microcapsules (microcapsules made of hydroxymethylcellulose, gelatin,polymethylmethacrylate, and the like), and made into components ofcolloidal drug delivery systems (liposomes, albumin microspheres,microemulsions, nano-particles, and nano-capsules) (for example, see“Remington's Pharmaceutical Science 16th edition” &, Oslo Ed. (1980)).Moreover, methods for making sustained-release drugs are known, andthese can be applied for nemolizumab or an equivalent thereof (Langer etal., J. Biomed. Mater. Res. (1981) 15, 167-277; Langer, Chem. Tech.(1982) 12, 98-105; U.S. Pat. No. 3,773,919; European Patent Application(EP) No. 58,481; Sidman et al., Biopolymers (1983) 22, 547-56; EP133,988).

The pharmaceutical compositions of the present disclosure can beadministered either orally or parenterally, but are preferablyadministered parenterally. Specifically, the pharmaceutical compositionsare administered to patients by injection or percutaneousadministration. Injections include, for example, intravenous injections,intramuscular injections, and subcutaneous injections, for systemic orlocal administration. The pharmaceutical compositions may be given tosites where inflammation is to be suppressed, or areas surrounding thesites by local infusion or intramuscular injection. In some embodiments,the pharmaceutical compositions are administered at the site of one ormore skin excoriations, or proximal to the site of one or more skinexcoriations.

The administration methods can be properly selected according to thepatient's age and condition. The single-administration dose can beselected, for example, from within the range of 0.0001 to 100 mg of theactive ingredient per kg body weight. Alternatively, for example, whenthe agents are administered to human patients, the dose of the activeingredient can be selected from within the range of 0.001 to 1,000 mg/kgbody weight. In some embodiments, the composition is formulated toadminister a dose containing, for example, about 0.01 to 50 mg/kg, about0.01 mg/kg to about 0.1 mg/kg, about 0.05 mg/kg to 0.15 mg/kg, about 0.1mg/kg to about 0.6 mg/kg, about 0.1 mg/kg to about 1 mg/kg, about 0.25mg/kg to about 0.75 mg/kg, about 0.4 mg/kg to about 0.8 mg/kg, about 0.4mg/kg to about 1.8 mg/kg, about 0.5 to about 2.5 mg/kg, about 0.8 mg/kgto about 2.2 mg/kg, about 1 mg/kg to about 2.5 mg/kg, about 1 mg/kg toabout 3.5 mg/kg, about 1 mg/kg to about 5 mg/kg, about 2 mg/kg to about4 mg/kg, about 2.5 mg/kg to about 10 mg/kg, about 5 mg/kg to about 10mg/kg, about 10 mg/kg to about 20 mg/kg, about 10 mg/kg to about 40mg/kg, about 20 mg/kg to about 50 mg/kg, about 25 mg/kg to about 75mg/kg, about 50 mg/kg to about 100 mg/kg, or about 100 mg/kg to about500 mg/kg, or about 100 mg/kg to about 1000 mg/kg body weight ofnemolizumab or an equivalent thereof. In preferred embodiments, the doseranges from about 0.01 mg/kg to about 0.1 mg/kg, about 0.1 mg/kg toabout 0.5 mg/kg, about 0.5 mg/kg to about 1.5 mg/kg, about 1.5 mg/kg toabout 2.5 mg/kg, or about 2.5 mg/kg to about 10 mg/kg. In someembodiments, the dose is about 0.01 mg/kg, about 0.02 mg/kg, about 0.03mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg,about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg,about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg,about 1.9 mg/kg, about 2 mg/kg, about 2.1 mg/kg, about 2.2 mg/kg, about2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, about 3 mg/kg, about 3.5 mg/kg,about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 15 mg/kg,about 25 mg/kg, about 50 mg/kg, about 75 mg/kg, about 100 mg/kg, about500 mg/kg, or about 1,000 mg/kg. In particular embodiments, theeffective amount of nemolizumab or the equivalent thereof is about 0.1mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg,or about 2.5 mg/kg. In a preferred embodiment, the dose is about 0.5mg/kg.

Methods of Treatment

In accordance with some embodiments, there are provided methods oftreating pruritus in in a subject having prurigo nodularis (PN), themethod comprising, consisting of, or consisting essentially ofadministering an effective amount of nemolizumab or an equivalentthereof to the subject.

In some embodiments, the pruritus is moderate to severe. In someembodiments of the methods, the subject has been diagnosed of PN for atleast 6 months. In particular embodiments of the methods, the subjecthas at least 20 nodules on his/her body with a bilateral distribution.In particular embodiments of the methods, the subject has prurigolesions on upper limbs, with or without lesions on the trunk or lowerlimbs. In particular embodiments of the methods, the pruritus has beenassigned a score of at least 7 on the Numerical Rating Scale (NRS). Inparticular embodiments of the methods, the mean of the worst dailyintensity of the NRS score is at least 7 over the previous 3 days. Inother particular embodiments of the methods, the mean of the worst dailyintensity of the NRS score is at least 7 over the previous week.

In some embodiments of the methods, the subject does not have atopicdermatitis. In some embodiments of the methods, the subject does nothave chronic pruritus resulting from a condition other than PN, such asscabies, insect bite, lichen simplex chronicus, psoriasis, acne,folliculitis, habitual picking, lymphomatoid papulosis, chronic actinicdermatitis, dermatitis herpetiformis, sporotrichosis, bullous disease.In some embodiments of the methods, the subject does not haveneuropathic or psychogenic pruritus, such as notalgia paresthetica,brachioradial pruritus, dilutional parasitosis, pathomimia.

An “effective amount” is an amount sufficient to effect beneficial ordesired results such as alleviating at least one or more symptom of PNand/or pruritus. An effective amount as used herein would also includean amount sufficient to delay the development of AD and/or pruritus,alter the course of an PN and/or pruritus symptom (for example sleepefficiency), or reverse a symptom of PN and/or pruritus. Thus, it is notpossible to specify the exact “effective amount.” However, for any givencase, an appropriate “effective amount” can be determined by one ofordinary skill in the art using only routine experimentation.

An effective amount can be administered in one or more administrations,applications or dosages. Such delivery is dependent on a number ofvariables including the time period for which the individual dosage unitis to be used, the bioavailability of the therapeutic agent, the routeof administration, etc. It is understood, however, that specific doselevels of the therapeutic agents of the present disclosure for anyparticular subject depends upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, and diet of the subject, the time ofadministration, the rate of excretion, the drug combination, and theseverity of the particular disorder being treated and form ofadministration. Treatment dosages generally may be titrated to optimizesafety and efficacy. The dosage can be determined by a physician andadjusted, as necessary, to suit observed effects of the treatment.Typically, dosage-effect relationships from in vitro and/or in vivotests initially can provide useful guidance on the proper doses forpatient administration. In general, one will desire to administer anamount of the compound that is effective to achieve a serum levelcommensurate with the concentrations found to be effective in vitro.Determination of these parameters is well within the skill of the art.These considerations, as well as effective formulations andadministration procedures are well known in the art and are described instandard textbooks.

Dosage regimens for treating CP and PN may comprise flat dosing (i.e.,administering the same dose repeatedly at pre-determined intervals) orcomprise a loading dose (i.e., administrating an initial dose that ishigher or different than subsequent, serial doses). For the purposes ofeither type of dosing regimen an effective dose may be administeredtopically, parenterally, subcutaneously, subdermally, intradermally, orintramuscularly.

In some embodiments, a loading dose and the subsequent serial doses maybe administered via the same route (e.g., subcutaneously), while in someembodiments, a loading dose and the subsequent serial doses may beadministered via different routes (e.g., parenterally andsubcutaneously, respectively). In some embodiments, the loading dose maybe about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg,about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110mg, about 115 mg, about 120 mg, or higher. In some embodiments, theloading dose may be 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, or higher. In someembodiments, the loading dose may be about 0.01 mg/kg, about 0.02 mg/kg,about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg,about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg,about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg,about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg,about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8mg/kg, about 1.9 mg/kg, about 2 mg/kg, about 2.1 mg/kg, about 2.2 mg/kg,about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg,about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, about 3 mg/kg, about3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 6 mg/kg,about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 15mg/kg, about 25 mg/kg, about 50 mg/kg, about 75 mg/kg, about 100 mg/kg,about 500 mg/kg, or about 1,000 mg/kg. In some embodiments, the loadingdose may be 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg,0.06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg, 0.1 mg/kg, 0.2 mg/kg,0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9mg/kg, 1 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg,1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2 mg/kg, 2.1 mg/kg, 2.2mg/kg, 2.3 mg/kg, 2.4 mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2.7 mg/kg, 2.8 mg/kg,2.9 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg, 6 mg/kg, 7mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 15 mg/kg, 25 mg/kg, 50 mg/kg, 75mg/kg, 100 mg/kg, 500 mg/kg, or 1,000 mg/kg. In some embodiments, theloading dose is administered as a single injection. In some embodiments,the loading dose is administered as multiple injections, which may beadministered at the same time or spaced apart at defined intervals.

The subsequent serial doses of a loading dose regimen are generallylower than the loading dose. For examples, in some embodiments, thedosing regimen may comprise a loading dose of 60 mg and a serial dose of30 mg, which may be administered a defined intervals of, for example,every 4 weeks. In some embodiments, the serial dose of a dosing regimenmay be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg,about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg,about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about110 mg, about 115 mg, about 120 mg, or higher. In some embodiments, theserial dose may be 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, or higher. In someembodiments, the serial dose may be about 0.01 mg/kg, about 0.02 mg/kg,about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg,about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg,about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg,about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg,about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8mg/kg, about 1.9 mg/kg, about 2 mg/kg, about 2.1 mg/kg, about 2.2 mg/kg,about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg,about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, about 3 mg/kg, about3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 6 mg/kg,about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 15mg/kg, about 25 mg/kg, about 50 mg/kg, about 75 mg/kg, about 100 mg/kg,about 500 mg/kg, or about 1,000 mg/kg. In some embodiments, the serialdose may be 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg,0.06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg, 0.1 mg/kg, 0.2 mg/kg,0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9mg/kg, 1 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg,1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2 mg/kg, 2.1 mg/kg, 2.2mg/kg, 2.3 mg/kg, 2.4 mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2.7 mg/kg, 2.8 mg/kg,2.9 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg, 6 mg/kg, 7mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 15 mg/kg, 25 mg/kg, 50 mg/kg, 75mg/kg, 100 mg/kg, 500 mg/kg, or 1,000 mg/kg.

For the purposes of a loading dose regimen, the first serial dose may beadministered 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8days, 9 days, 10 days, 11 days, 12 days, 13 days, 1 week, 2 weeks, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeksafter the initial loading dose. In some embodiments, the first serialdose is administered 4 weeks after the initial loading dose. In someembodiments, the subsequent serial doses are administered once every 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks. In someembodiments, the serial doses are spaced 4 weeks apart (i.e.,nemolizumab or an equivalent thereof is administered once every 4weeks).

In some embodiments, the dose of nemolizumab or an equivalent thereofadministered to the subject is within the range of 0.001 to 1,000 mg/kgbody weight of the subject. In some embodiments, the dose ranges fromabout 0.01 to 50 mg/kg, about 0.01 mg/kg to about 0.1 mg/kg, about 0.05mg/kg to 0.15 mg/kg, about 0.1 mg/kg to about 0.6 mg/kg, about 0.1 mg/kgto about 1 mg/kg, about 0.25 mg/kg to about 0.75 mg/kg, about 0.4 mg/kgto about 0.8 mg/kg, about 0.4 mg/kg to about 1.8 mg/kg, about 0.5 toabout 2.5 mg/kg, about 0.8 mg/kg to about 2.2 mg/kg, about 1 mg/kg toabout 2.5 mg/kg, about 1 mg/kg to about 3.5 mg/kg, about 1 mg/kg toabout 5 mg/kg, about 2 mg/kg to about 4 mg/kg, about 2.5 mg/kg to about10 mg/kg, about 5 mg/kg to about 10 mg/kg, about 10 mg/kg to about 20mg/kg, about 10 mg/kg to about 40 mg/kg, about 20 mg/kg to about 50mg/kg, about 25 mg/kg to about 75 mg/kg, about 50 mg/kg to about 100mg/kg, or about 100 mg/kg to about 500 mg/kg, or about 100 mg/kg toabout 1000 mg/kg body weight of nemolizumab or an equivalent thereof. Inpreferred embodiments, the dose ranges from about 0.01 mg/kg to about0.1 mg/kg, about 0.1 mg/kg to about 0.5 mg/kg, about 0.5 mg/kg to about1.5 mg/kg, about 1.5 mg/kg to about 2.5 mg/kg, or about 2.5 mg/kg toabout 10 mg/kg. In some embodiments, the dose is about 0.01 mg/kg, about0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9mg/kg, about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg,about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg,about 1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg, about 2.1 mg/kg, about2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, about 3 mg/kg,about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 6mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg,about 15 mg/kg, about 25 mg/kg, about 50 mg/kg, about 75 mg/kg, about100 mg/kg, about 500 mg/kg, or about 1,000 mg/kg. In particularembodiments, the effective amount of nemolizumab or the equivalentthereof is about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5mg/kg, about 2 mg/kg, or about 2.5 mg/kg. In a preferred embodiment, thedose is about 0.5 mg/kg.

In some embodiments, the dose of nemolizumab or an equivalent thereofadministered to the subject is within the range of 1 to 100 mg, 25 to 75mg, 30 to 60 mg, 40 to 80 mg, 20 to 80 mg, 1 to 25 mg, 1 to 50 mg, 10 to90 mg, 15 to 85 mg, or ranges there between. In some embodiments, thedose may be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105mg, about 110 mg, about 115 mg, about 120 mg, or higher. In someembodiments, the dose may be 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, or higher.

In particular embodiments, a loading dose of about 60 mg of nemolizumabor an equivalent thereof may be administered to a subject in needthereof, followed by subsequent serial doses of nemolizumab of anequivalent thereof at about 30 mg once every 4 weeks.

In some embodiments of the methods, the nemolizumab or the equivalentthereof is administered by a topical or parenteral route. In someembodiments of the methods, the nemolizumab or the equivalent thereof isadministered subcutaneously. In some embodiments, the dose isadministered subcutaneously at or proximal to a site of one or morenodules.

In some embodiments, nemolizumab or the equivalent thereof isadministered daily, every other day, twice per week, three times perweek, four times per week, five times per week, six times per week, onceper week, once every two weeks, once every three weeks, once every fourweeks, once every five weeks, once every six weeks, once every sevenweeks, once every eight weeks, once every nine weeks, once every 10weeks, once every 11 weeks, once every 12 weeks, twice per year, onceper year, and/or as needed based on the appearance of symptoms of atopicdermatitis or pruritus (e.g., CP or PN). In preferred embodiments,nemolizumab or the equivalent thereof is administered every four weeksor every eight weeks.

In some embodiments, the duration of treatment is about one day, aboutone week, about two weeks, about three weeks, about four weeks, aboutfive weeks, about six weeks, about seven weeks, about eight weeks, aboutnine weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks,about 18 weeks, about 19 weeks, about 20 weeks, about 24 weeks, about 30weeks, about 36 weeks, about 40 weeks, about 48 weeks, about 50 weeks,about one year, about two years, about three years, about four years,about five years, or as needed based on the appearance of symptoms ofatopic dermatitis or pruritus (e.g., CP or PN). In preferredembodiments, duration of treatment is about 12 weeks to about 24 weeks,about 12 to about 36 weeks, about 12 to about 48 weeks, or about 24 toabout 36 weeks.

In accordance with some embodiments, there are provided uses ofnemolizumab or an equivalent thereof in the manufacture of a medicamentfor the treatment of pruritus s in a subject having prurigo nodularis(PN).

In some embodiments of the uses, the pruritus is moderate to severe. Insome embodiments of the uses, the subject has been diagnosed of PN forat least 6 months. In particular embodiments of the uses, the subjecthas at least 20 nodules on his/her body with a bilateral distribution.In particular embodiments of the uses, the subject has prurigo lesionson upper limbs, with or without lesions on the trunk or lower limbs. Inparticular embodiments of the methods, the pruritus has been assigned ascore of at least 7 on the Numerical Rating Scale (NRS). In particularembodiments of the uses, the mean of the worst daily intensity of theNRS score is at least 7 over the previous 3 days. In other particularembodiments of the uses, the mean of the worst daily intensity of theNRS score is at least 7 over the previous week.

In some embodiments of the uses, the subject does not have atopicdermatitis. In some embodiments of the uses, the subject does not havechronic pruritus resulting from a condition other than PN, such asscabies, insect bite, lichen simplex chronicus, psoriasis, acne,folliculitis, habitual picking, lymphomatoid papulosis, chronic actinicdermatitis, dermatitis herpetiformis, sporotrichosis, bullous disease.In some embodiments of the uses, the subject does not have neuropathicor psychogenic pruritus, such as notalgia paresthetica, brachioradialpruritus, dilutional parasitosis, pathomimia.

EXAMPLES

Example 1 Determine Efficacy of Nemolizumab in the Treatment of Pruritusof PN Patients.

A multi-center (20 sites in EU & US), randomized, double-blinded,placebo-controlled, parallel group study was conducted comprisingapproximately 70 randomized patients in 2 arms (35 per arm) stratifiedon background of atopy. Enrolled patients received subcutaneousnemolizumab or placebo at a dose of 0.5 mg/kg every 4 weeks. Thepatients were selected based on the following criteria.

Inclusion Criteria:

1. Male or female of at least 18 years at screening.

2. Clinical diagnosis of PN for at least 6 months with: (a) Prurigolesions on upper limbs with or without lesions on the trunk or lowerlimbs, and (b) at least 20 nodules on the entire body with a bilateraldistribution

3. Severe pruritus on a Numerical Rating Scale (NRS). NRS is determinedboth by screening visit and baseline visit. Screening visit: Mean of theworst daily intensity of the NRS score is ≥7 over the previous 3 days.Baseline visit: Mean of the worst daily intensity of the NRS score is ≥7over the previous week.

4. Female subjects must fulfill one of the criteria: (a) Female subjectsof non-childbearing potential (postmenopausal, i.e. absence of menstrualbleeding for 1 year prior to screening, without any other medicalreason, hysterectomy or bilateral oophorectomy); (b) Female subjects ofchildbearing potential who agree to a true abstinence (when in line withthe preferred and usual lifestyle of the subject), or to use aneffective method of contraception throughout the clinical trial and for120 days after the last study drug administration.

Patients with the following conditions are excluded.

Exclusion Criteria:

1. Chronic pruritus resulting from another condition than PN such asscabies, insect bite, lichen simplex chronicus, psoriasis, acne,folliculitis, habitual picking, lymphomatoid papulosis, chronic actinicdermatitis, dermatitis herpetiformis, sporotrichosis, bullous disease.

2. Unilateral lesions of prurigo (e.g only one arm affected).

3. Cutaneous bacterial or viral infection within 1 week before thebaseline visit.

4. Infection requiring treatment with oral or parenteral antibiotics,antivirals, antiparasitics or antifungals within 1 week before thescreening visit, or during the screening period, unless completelyresolved at the screening/baseline visits respectively.

5. Any uncontrolled or serious disease, or any medical or surgicalcondition, that may either interfere with the interpretation of theclinical trial results and/or put the subject at significant riskaccording to Investigator's judgment (e.g. solid cancer, AIDS, seriousor uncontrolled cardiac disease) at Screening or Baseline.

Any active dermatoses that would need immediate therapy.

7. Active atopic dermatitis or known with recurrent flares of atopicdermatitis

8. Neuropathic and psychogenic pruritus (notalgia paresthetica,brachioradial pruritus, dilutional parasitosis, pathomimia).

9. Positive serology results hepatitis B surface antigen (HBsAg) orhepatitis B core antibody (HBcAb), hepatitis C antibody or HumanImmunodeficiency virus (HIV) antibody) at the screening visit.

10. Abnormal lab criteria listed below, at the screening visit: ElevatedALT/AST≥3 ULN, Elevated CPK>1.5 ULN, Neutrophil count<1.5×10³/μl,Creatinine clearance<60 ml/min/1.73 m²;

11. Medical history of asthma that fulfill any or more of theconditions: (i) had an asthma exacerbation requiring hospitalization inthe last 12 months before screening visit; (ii) Whose asthma has notbeen well-controlled (i.e. symptoms>2 days per week, nighttimeawakenings>1-3 times per week, or some interference with normalactivities) during the last 3 months before the screening visit; PEF<80%of the predicted value at screening or baseline visit.

12. Latent or active TB, as determined by a positive Quantiferon-basedTB test result at screening visit.

13. Having received any of forbidden treatments within the specifiedtime frame prior to the baseline visit:

TABLE 1 Forbidden Therapies Wash-out periods Topical treatmentsCalcineurin inhibitors (tacrolimus, pimecrolimus), 2 weeks TCS, vitaminD analogs, PDE-4 inhibitors Any topical treatment other than moisturizer(e.g 2 weeks capsaicin, cryotherapy) Emollients or moisturizer withmenthol, capsaicine, 1 week polidocanol or other having “anti-itch”claim Systemic treatments Corticosteroids oral, injectable 4 weeksimmunosuppressive or immunomodulatory drugs (e.g, 8 weeks orazathioprine, methotrexate, thalidomide, cyclosporine 5 half-lives(whichever is longer) Antihistamines 1 week Phototherapy 4 weeksRoxitromycin, erythromycin 1 week Opiods (naltrexone, naloxone,nalbuphine etc), NK1 4 weeks or receptor antagonists (aprepitant),antiepileptics 5 half-lives (gabapentin, pregabalin) (whichever islonger) Biologics, Retinoids 8 weeks or 5 half-lives (whichever islonger) Live vaccine 4 weeks Drugs with sedative effect such asbenzodiazepines, 3 months imidazopyridines, hydroxizine barbiturates, orsedative anti-depressants such as amitryptiline, paroxetine, except ifthese treatments were taken at a stable dose for at least 3 monthsbefore screening

If deemed to be medically necessary by the Investigator, rescuetreatments for pruritus could be associated to the study drug from Day29. All efficacy and safety assessments should be completed beforestarting the rescue treatments.

TABLE 2 Rescue Therapies Rescue therapies Action to be takenAntihistamines, association of Continue the study drug antihistaminesand TCS of mid- potency cyclosporine, thalidomide, gabapentin,Discontinue the study drug phototherapy, etc . . .

Endpoints:

The primary endpoint of the study was a percent reduction from baseline(BL) in pruritus NRS at week 4.

The secondary endpoints of the study was a reduction at every visit upto 18 weeks, characterized by NRS, VRS, or DPS. Safety evaluations werealso conducted at the secondary endpoint. Prurigo remission wascharacterized by prurigo activity score (PAS) and IGA. Pharmacokinetic(PK) profile of PN patients was measured. Pharmacodynamic (PD) profileof PN patients was measured in patients' blood, biopsies, and D-squamessamples. Quality of life of PN patients was measured by DLQI. Actigraphywas applied to assess sleep improvement and scratching (by Actiwatch).Photographs of PN patients were taken by fotofinder in selected centers.

The results of the clinical study are presented in the tables below.

TABLE 3 Demographics and baseline characteristics Nemolizumab Placebo0.5 mg/kg Total (N = 36) (N = 34) (N = 70) Gender Male 14 (38.9%) 15(44.1%) 29 (41.4%) Female 22 (61.1%) 19 (55.9%) 41 (58.6%) Race White 35(97.2%) 33 (97.1%) 68 (97.1%) Black/African 1 (2.8%) 1 (2.9%) 2 (2.9%)American Asian 0 0 0 Other 0 0 0 Age (years) Mean (SD) 52.4 (17.47) 59.7(13.16) 56.0 (15.85) Range 20-77 26-85 20-85 Weight 36  34  70  Mean(SD) (kg) 80.30 (20.716) 81.61 (21.766) 80.94 (21.088) Note: Percentagesare based on the number of subjects having a non-missing value in therespective treatment arm.

As shown in Table 3, the placebo group and the nemolizumab treated groupin the study presented comparable composition in gender, race, age, andweight.

TABLE 4 Baseline clinical disease characteristics Nemolizumab Placebo0.5 mg/kg Total (N = 36) (N = 34) (N = 70) Mean Prurigo baselineassessment 22.4 (17.50) 17.1 (13.39) 19.8 (15.76) (PAS) (SD) Backgroundof atopy  1 Presence 6 (16.7%) 5 (14.7%) 1 (15.7%) Absence 30 (83.3%) 29(85.3%) 59 (84.3%) Number of nodules on the entire body n (%) 20-100 21(58.3) 21 (61.8) 42 (60.0) >100 15 (41.7) 13 (38.2) 28 (40.0) Weeklypeak pruritus NRS Mean ± SD 8.4 (1.18) 8.4 (1.19) 8.4 (1.17) Range (7-9)(8-9) (8-9) Weekly avg pruritus NRS 34 33 67 Mean (SD) 7.9 (1.28) 7.8(1.66) 7.9 (1.47) Investigator Global Assessment (IGA) n (%) Moderate 22(61.1) 16 (47.1) 38 (54.3) Severe 14 (38.9) 18 (52.9) 32 (45.7) DLQIbaseline score (range 0-30) Mean ± SD 15.8 ± 6.0 16.9 ± 7.5

As shown in Table 4, the placebo group and the nemolizumab treated groupin the study presented comparable baseline level of pruritus, measuredby number of nodules on the entire body, weekly peak pruritus numericalrating scale (NRS) score, weekly average pruritus NRS score, andInvestigator's global assessment (IGA) score.

TABLE 5 Incidence of Rescue Medication Nemolizumab Placebo 0.5 mg/kgTotal (N = 36) (N = 34) (N = 70) Subject with ≥1 rescue 4 (11.1%) 2(5.9%) 6 (8.6%) medications during treatment period Type of rescueduring treatment period: Topical rescue medication (n) 4 (11.1%) 0 4(5.7%) Systemic rescue medication (n) 3 (8.3%)  2 (5.9%) 5 (7.1%)

As shown in Table 5, the placebo group has more incidence of topicalrescue medication and systemic rescue medication.

The efficacy results are shown by FIGS. 2-15. In particular, at primaryendpoint, the nemolizumab treatment significantly reduced pruritus atweek 4, as illustrated by the percentage change from baseline in weeklyaverage peak pruritus NRS (FIG. 2). Thus, nemolizumab treatment at thedosage of 0.5 mg/kg is superior to placebo (−38%, 95% CI=[−51%, −25%]and statistically significant (p<0.001) at Week 4.

At secondary endpoints, the nemolizumab treatment group consistentlyshows more reduced pruritus throughout the 18 weeks study, as evidencedby both the percentage change (FIG. 3) and the absolute change (FIG. 4)in peak pruritus NRS, and the results are statistically significant(p<0.001). The same results were also observed both in patients withoutor with atopic dermatitis (FIGS. 5 and 6).

Investigators' Global Assessment (IGA) scores range from 0 (clear) to 4(severe disease) and are presented as a percentage of patients in theindicated population. A much higher percentage of patients treated withnemolizumab compared to the placebo group achieved IGA success (IGA 0/1)(FIG. 7). In addition, IGA distribution shows that the nemolizumabtreatment group has consistently higher percentage of patients withlower IGA than the placebo group (FIG. 8). The findings arestatistically significant (p<0.05) at Week 12 and Week 18.

Verbal rating scale (VRS) is a monodimensional scale that allowspatients to describe their itch intensity by means of gradually risingadjectives (1=no itch, and 4=very severe itch). In other words, thenemolizumab treatment group shows consistently higher percentage changein negative value, which translates into more reduced itchinessthroughout the 18 weeks study compared to the placebo group (FIG. 9).The results are statistically significant (p<0.001).

Dermatology Life Quality Index (DLQI) scores range from 0 to 30, withhigher scores indicating a lower quality of life. As shown in FIG. 10,the nemolizumab treatment group has a higher percentage of respondersrating DLQI≥4 compared to the placebo group both at week 4 and week 12.As shown in FIG. 11, change from baseline in DLQI is statisticallysignificant (p<0.01) in favor of nemolizumab at week 4 but not at week12.

Full body images were taken of representative patients. As shown byFIGS. 12A-12D, 13A-13D, and 14A-14D, nemolizumab treatment significantlyreduced the number of nodules on patient's body after 16 weeks.

Preliminary Safety Results

As shown in Tables 6 and 7, the nemolizumab treatment group and theplacebo group shows comparable numbers of treatment emergent adverseevents (TEAEs) of all causes, and comparable incidence of TEAEs bysystem organ class (SOC) of all causes. Overall nemolizumab was welltolerated.

TABLE 6 Safety-overall summary of treatment emergent adverse events(TEAEs) of all causes Nemolizumab Placebo 0.5 mg/kg Total (N = 36) (N =34) (N = 70) Number of TEAEs 69 77  146 Subjects with at least one 24(66.7%) 23 (67.6%) 47 (67.1%) TEAE Serious TEAE 3 (8.3%) 4 (11.8%) 7(10.0%) Severe TEAE 1 (2.8%) 5 (14.7%) 6 (8.6%) Fatal TEAE  0 0  0 TEAEleading to temporary 1 (2.8%) 0 1 (1.4%) drug discontinuation TEAEleading to permanent 1 (2.8%) 2 (5.9%) 3 (4.3%) drug discontinuationTEAE leading to withdrawal 2 (5.6%) 2 (5.9%) 4 (5.7%)

TABLE 7 Incidence of TEAEs by System Organ Class (SOC) (>5%), all causesNemolizumab Placebo 0.5 mg/kg Total (N = 36) (N = 34) (N = 70)Infections and infestation 12 (33.3%) 10 (29.4%) 22 (31.4%) Skin andsubcutaneous 12 (33.3%) 10 (29.4%) 22 (31.4%) tissue disordersGastrointestinal disorders 5 (13.9%) 7 (20.6%) 12 (17.1%)Musculoskeletical and 5 (13.9%) 6 (17.6%) 11 (15.7%) connective tissuedisorders General disorders and 4 (11.1%) 5 (14.7%) 9 (12.9%)administration site conditions Injury, poisoning and 2 (5.6%) 4 (11.8%)6 (8.6%) procedural complication Renal and urinary disorders 2 (5.6%) 2(5.9%) 4 (5.7%) Nervous system disorders 1 (2.8%) 2 (5.9%) 3 (4.3%)Respiratory, thoracic and 3 (8.3%) 0 3 (4.3%) mediastatial disordersBlood and lymphatic 2 (5.6%) 0 2 (2.9%) system disorders Metabolism andnutrition 0 2 (5.9%) 2 (2.9%) disorders Psychiatric disorders 2 (5.6%) 02 (2.9%) Vascular disorders 2 (5.6%) 0 2 (2.9%)

1.-29. (canceled)
 30. A method of treating skin lesions and pruritus ina subject having chronic prurigo (CP), comprising administering about 30mg to about 60 mg of nemolizumab or an equivalent thereof to thesubject.
 31. The method of claim 30, wherein the subject has prurigonodularis (PN).
 32. The method of claim 31, wherein the subject has beendiagnosed of PN for at least about 6 months.
 33. The method of claim 30,wherein the subject has at least about 20 nodules on his/her body with abilateral distribution.
 34. The method of claim 30, wherein the subjecthas prurigo lesions on upper limbs.
 35. The method of claim 30, whereinthe pruritus has been assigned a score of at least 4 on the NumericalRating Scale (NRS).
 36. The method of claim 30, wherein the pruritus hasbeen assigned a score of at least 7 on the Numerical Rating Scale (NRS).37. The method of claim 30, wherein the subject does not have atopicdermatitis.
 38. The method of claim 30, wherein the nemolizumab or theequivalent thereof is administered to the subject according to a flatdosing regimen.
 39. The method of claim 30, wherein the nemolizumab orthe equivalent thereof is administered to the subject according to aloading dose regimen.
 40. The method of claim 30, wherein 30 mg or 60 mgof nemolizumab or the equivalent thereof is administered to the subject.41. The method of claim 30, wherein the nemolizumab or the equivalentthereof is administered to the subject once every four weeks.
 42. Themethod of claim 30, wherein the nemolizumab or the equivalent thereof isadministered subcutaneously.
 43. A method of treating prurigo nodularis(PN), comprising subcutaneously administering about 30 mg to about 60 mgof nemolizumab to a subject with PN.
 44. The method of claim 43, whereinthe subject has been diagnosed of PN for at least about 6 months. 45.The method of claim 43, wherein the subject has at least about 20nodules on his/her body with a bilateral distribution.
 46. The method ofclaim 43, wherein the subject has prurigo lesions on upper limbs. 47.The method of claim 43, wherein the pruritus has been assigned a scoreof at least 4 on the Numerical Rating Scale (NRS).
 48. The method ofclaim 43, wherein the pruritus has been assigned a score of at least 7on the Numerical Rating Scale (NRS).
 49. The method of claim 43, whereinthe subject does not have atopic dermatitis.
 50. The method of claim 43,wherein the nemolizumab is administered to the subject according to aflat dosing regimen.
 51. The method of claim 43, wherein the nemolizumabis administered to the subject according to a loading dose regimen. 52.The method of claim 43, wherein 30 mg or 60 mg of nemolizumab or theequivalent thereof is administered to the subject.
 53. The method ofclaim 43, wherein the nemolizumab or the equivalent thereof isadministered to the subject once every four weeks.
 53. The method ofclaim 43, wherein 60 mg of nemolizumab is administered to the subjectonce every four weeks.
 54. The method of claim 43, wherein a firstadministration comprises 60 mg of nemolizumab and subsequentadministrations comprise 30 mg of nemolizumab, wherein any subsequentadministration is given once every four weeks.